IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases

Amina El Ayadi, Michael J. Zigmond, Amanda D. Smith

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 µg) 6 h prior to infusion of 4 µg 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 µg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades.

Original languageEnglish (US)
Pages (from-to)1863-1873
Number of pages11
JournalExperimental Brain Research
Volume234
Issue number7
DOIs
StatePublished - Jul 1 2016

Fingerprint

Dopaminergic Neurons
Somatomedins
Oxidative Stress
Phosphotransferases
Oxidopamine
Substantia Nigra
Parkinson Disease
Corpus Striatum
Tyrosine 3-Monooxygenase
Glycogen Synthase Kinase 3
Blood-Brain Barrier
Phosphatidylinositol 3-Kinases
Brain Injuries
Dopamine
Animal Models
Phenotype
Peptides

Keywords

  • 6-OHDA
  • Akt
  • CREB
  • ERK1/2
  • GSK-3Beta
  • Parkinson’s disease
  • Striatum

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

IGF-1 protects dopamine neurons against oxidative stress : association with changes in phosphokinases. / Ayadi, Amina El; Zigmond, Michael J.; Smith, Amanda D.

In: Experimental Brain Research, Vol. 234, No. 7, 01.07.2016, p. 1863-1873.

Research output: Contribution to journalArticle

@article{64158f70f0774bdb9129d4933509c472,
title = "IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases",
abstract = "Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 µg) 6 h prior to infusion of 4 µg 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 µg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades.",
keywords = "6-OHDA, Akt, CREB, ERK1/2, GSK-3Beta, Parkinson’s disease, Striatum",
author = "Ayadi, {Amina El} and Zigmond, {Michael J.} and Smith, {Amanda D.}",
year = "2016",
month = "7",
day = "1",
doi = "10.1007/s00221-016-4572-1",
language = "English (US)",
volume = "234",
pages = "1863--1873",
journal = "Experimental Brain Research",
issn = "0014-4819",
publisher = "Springer Verlag",
number = "7",

}

TY - JOUR

T1 - IGF-1 protects dopamine neurons against oxidative stress

T2 - association with changes in phosphokinases

AU - Ayadi, Amina El

AU - Zigmond, Michael J.

AU - Smith, Amanda D.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 µg) 6 h prior to infusion of 4 µg 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 µg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades.

AB - Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 µg) 6 h prior to infusion of 4 µg 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 µg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades.

KW - 6-OHDA

KW - Akt

KW - CREB

KW - ERK1/2

KW - GSK-3Beta

KW - Parkinson’s disease

KW - Striatum

UR - http://www.scopus.com/inward/record.url?scp=84975263365&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975263365&partnerID=8YFLogxK

U2 - 10.1007/s00221-016-4572-1

DO - 10.1007/s00221-016-4572-1

M3 - Article

C2 - 26894890

AN - SCOPUS:84975263365

VL - 234

SP - 1863

EP - 1873

JO - Experimental Brain Research

JF - Experimental Brain Research

SN - 0014-4819

IS - 7

ER -